Reclassification of BRCA2 Variants of Uncertain Significance Using Saturation Genome Editing Combined with Clinical Phenotypes in Breast Cancer.

BRCA2

Published saturation genome editing (SGE) scores applied to variants of uncertain significance in exons 15 to 26 of BRCA2, then compared with the clinical phenotypes of carriers

This study evaluates the pathogenicity of BRCA2 variants of uncertain significance located in the functionally critical exons 15 to 26, using published saturation genome editing (SGE) data, and reclassifies them by integrating clinical phenotypes. Among 15,092 breast cancer patients, 457 distinct BRCA2 variants of uncertain significance were identified in 1,051 carriers. Based on SGE scores, 88 of these variants (187 carriers) were functionally assessed: 15 were reclassified as functionally pathogenic (20 carriers), 66 as functionally benign (154 carriers) and 7 remained variants of uncertain significance (13 carriers). Compared with non-carriers, carriers of functionally pathogenic variants had a higher prevalence of a family history of any cancer (65.0% versus 31.1%; p = 0.002), particularly breast and/or ovarian cancer (35.0% versus 10.0%; p = 0.002), with a trend towards more bilateral breast cancer (10.0% versus 2.4%; p = 0.085), whereas carriers of functionally benign variants had clinicopathological characteristics similar to non-carriers. The authors conclude that the SGE-based functional score is a reliable approach for reclassifying BRCA2 variants and that integrating it with clinical phenotypes improves the accuracy of pathogenicity assessment.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Crossing a published functional score with clinical phenotype gives an independent second look at variants that remained of uncertain significance, and the picture is coherent on both sides: an excess of family history for functionally pathogenic variants, a non-carrier profile for functionally benign ones. The categories must nonetheless be read for what they are: they rest on previously published SGE scores rather than on a new experiment, and phenotypic validation relies on only 20 carriers of functionally pathogenic variants, with a non-significant difference in bilateral breast cancer (p = 0.085). On an exome or a genome, where BRCA2 is already sequenced, this interpretation step is what decides the result returned to the patient, and the abstract mentions no classification under a formal framework.

Analysis by Dr Thibaut Benquey